This application consists of a comprehensive progress report and a request for an additional three years of funding for years 3, 4, and 5 of a five year grant. The work concerns the location of the antibody combining site within immunoglobulin molecules. In addition, the location and nature of the idiotypic determinants is being probed. To this end the heavy chain variable regions of 10 human myeloma proteins have been completely sequenced. In addition, the heavy chains of various human myeloma proteins with antibody activity have been studied and their structures compared to the randomly chosen myeloma proteins. The conclusions of the work to date are as follows: 1) The variability within the human heavy chain variable region is primarily located within three "hot spots." 2) The hypervariable regions are primarily responsible for the antibody specificity of an immunoglobulin molecule. 3) The location of the so-called "ligand modifiable idiotypes" most likely residues in these hypervariable regions. Continued correlation of the structure of these molecules with function and specificity is the prime goal of our studies.